Psoriasis is perhaps the most prevalent proliferative skin disease. A recent review article, "Research Needs in 11 Major Areas in Dermatology", J Invest Derm 73:402-413, 1979, reports estimates that up to 4% of the U.S. population suffers from psoriasis. Psoriasis is believed to be a multifactorial genetic disease. Individuals that are genetically predisposed to psoriasis susceptibility develop the disease either spontaneously or in an area of damaged skin. The disease is characterized by uncontrolled benign growth of the epidermis and psoriatic epidermis exhibits (1) a marked increase in proliferation and (2) reduced terminal differentiation. Accordingly, much of the research on the etiology and treatment of psoriasis has focused on the factors that control epidermal growth and differentiation and on the pharmocological modulation of one or more of those factors.
A variety of therapies are currently used to treat psoriasis including dialysis, photochemotherapy, systemic chemotherapy, and topical chemotherapy. Topical chemotherapy is probably the most widely used. Tar, retinoids, anthralin, corticosteroids and antimetabolites are among the agents currently used to treat psoriasis. Cyclic adenosine monophosphate (cAMP) is among the factors that are believed to be critical regulators of cell physiology and, correlatively, derangement of the epidermal cAMP system is associated with psoriasis. Accordingly, cAMP and many derivatives thereof have been considered as antipsoriatic agents. In this regard U.S. Pat. Nos. 4,007,268 and 4,207,315 propose the use of certain 9-.beta.-D-ribofuranosyladenine-3',5'-cyclic phosphates to treat proliferative skin diseases such as psoriasis. These compounds are analogs of the cyclic nucleotides that are used in the present invention. Comparative tests between some of these analogs and the nucleotides used in the present invention show the latter to have unexpected superior antipsoriatic activity of the analogs that were tested.
U.S. Pat. No. 4,058,659 describes a genus of 6,8-substituted-9-.beta.-D-ribofuranosylpurine-3', 5'-cyclic phosphates that includes some, but not all, of the cyclic nucleotides that are used in the present invention. The compounds of the genus are analogs of the naturally occurring purine nucleotides and are said to be more resistant to phosphodiesterase attack than the natural compounds. The compounds are described as exhibiting, inter alia, phosphodiesterase inhibition, protein kinase activation, and adenyl cyclase inhibition activities. In this regard the first two activities--phosphodiesterase inhibition and protein kinase activation--are generally considered to be characteristic of compounds that are useful to treat psoriasis. However, applicant's findings show that topical antipsoriatic activity cannot, however, be inferred from such activities because all compounds that possess such activities are not practical antipsoriatic agents. The third activity--adenyl cyclase inhibition--is not characteristic of such compounds and indeed would be more characteristic of compounds that promote proliferative skin diseases.
As described in detail below, applicants' investigations also clearly indicate that the effectiveness of a given cAMP analog as a topical antipsoriatic agent cannot be predicted from the chemical structure of the analog.